1. Field of the Invention
The present invention concerns the treatment of glomerulonephritis. More particularly, this invention is directed to treating patients suffering from glomerulonephritis by administering to such patients an effective amount of nitrendipine.
2. Background Information
Glomerulonephritis, an immune complex disease, is often a poststreptococcal disease.
Glomerulonephritis may be initiated by antigen-antibody complexes on the glomerular basement membrane. The most important antigen is probably in the streptococcal protoplast membrane. In acute nephritis, there is blood and protein in the urine, edema, high blood pressure, and nitrogen retention; serum complement levels are low. A few patients die; some develop chronic glomerulonephritis with ultimate kidney failure; the majority recover completely.
At present, no rational treatment is available for progressive glomerular disease. Strategies for protective intervention should be based upon knowledge of etiologic and pathogenetic factors that determine the course of the glomerular lesions. While such information is currently fragmented or lacking, it appears reasonable to consider that the progressive glomerular changes are the result of an ongoing inflammatory response to injury of glomerular structures.
The initiating types of injury to the glomerulus may be immunological, metabolic, toxic, or physical in nature. In states of loss of functioning nephrons, glomerular hypertension has been suggested to be a pathogenetic factor that contributes to the perpetuation of glomerular injury, no matter of what initial etiology (Brenner, B. M., "Nephron Adaptation of Renal Injury or Ablation.", Am. J. Physiol., (1985), 249F324-F337).
Elevation of glomerular capillary hydraulic pressure (P.sub.GC) has been shown to occur as a compensatory mechanism to maintain overall glomerular filtration (Brenner, supra; Hostetter, T. H., Olson J. L., Rennke, H. G., Venkatachalam, M. A., Brenner, B. M., "Hyperfilitration in Remnant Nephrons: A Potentially Adverse Response to Renal Ablation", Am. J. Physiol., (1981), 241, F185-F193).
In analogy to the injurious effects of increased blood pressure on arterial and arteriolar walls, glomerular hypertension has been considered to damage the glomerulus in an as yet ill-defined manner. Conceptually, the continued proliferation of glomerular cells and extracellular matrix constitute the inflamatory response to such injury. Among the cells that may participate in this response one should consider the glomerular endothelial, mesangial, and epithelial cells, as well as blood-derived cells, e.g., leukocytes and platelets.
A rational for the use of calcium entry blockers (CEB) for protective intervention in progressive glomerular disease is based on several actions of this group of agents documented in other cell systems. First, CEB have general vasodilatory effects (Loutzenhiser, R., Epstein, M., "Effects of Calcium Anatagonists on Renal Hemodynamics", (Editorial review)., Am. J. Physiol., (1985), 249, F619-F629; Fleckenstein, A., Frey, M., Zorn, J., Fleckenstein-Gruen, G., "Experimental Basis for Long-Term Therapy of Arterial Hypertension with Calcium Anatagonists", Am. J. Cardiol., (1985), 56, 3H-14H).
In particular, CEB have been shown to normalize P.sub.GC after it had been raised by infusion of angiotensin II(Ichikawa, I., Miele, J. F., Brenner, B. M., "Reversal of Renal Cortical Actions of Angiotensin II by Verapamil and Manganese, Kidney Int., (1979), 16, 136-147).
Second, recent cell culture studies have revealed that CEB may interfere with the activation of macrophages (Wright, B., Zeidman, I., Greig, R., Poste, G., "Inhibition of Macro Phage Activation by Calcium Channel Blockers and Calmodulin Antagonists", Cell Immunol., (1985), 95, 46-53) and platelets (Mehta, J. L., "Influence of Calcium Channel Blockers on Platelet Function and Arachidonic Acid Metabolism", Am. J. Cardiol., (1985), 56, 158B-164B).
Third, the release of platelet activating factor, a powerful inflammatory mediator, from leukocytes has been found suppressed in the presence of CEB (Jouvin-Marche, E., Cerrina, J., Coeffier, E., Duroux, P., Benveniste, J., "Effect of the Ca.sup.2+ -antagonist Nifedipine on the Release of Platelet-activating Factor (PAF-acether), Slow-Reacting Substance and Beta-glucuronidase from Human Neutrophilis", Eur J. Pharmacol., (1983), 89, 19-26).
Fourth, recent work by Heinle and Reich has indicated that the CEB, verapamil, prevents growth-promoting effects of serum on cultured vascular smooth muscle cells (Heinle, H., Reich A., "Inhibition by Verapamil of the Medium Change Induced Stimulation of Cultured Vascular Smooth Muscle Cells", Arzneim Forsch, (1985), 35, 1811-1812).
According to a recent publication by Busse et al. (J. Lab. Clin. Med., 109, 422-428, (1987)), nitrendipine inhibits ragweed antigen E.-dependent basophil histamine release.